The ability to raise an immune response to specific antigens has recently been shown to be under genetic control, linked to the major histocompatibility complex (MHC) in several species studied. In the mouse, a number of synthetic antigens have been found subject to this H-2 linked control, but only a few natural globular proteins have been studied as antigens, among these, staphylococcal nuclease. We have now tried to delineate the individual antigenic determinants on this protein which are responsible for this genetic control of the immune response in inbred strains of mice, in order to better understand the mechanisms involved. We have found that a single peptide fragment of the protein appears to be under the same control as the whole molecule. Furthermore when antibodies made to the whole nuclease molecule are studied for their specificity, we have found that the H-2 linked immune response genes can control the response to individual determinants on the same molecule independently of one another, and therefore may be involved in the selection of specific B lymphocytes rather than only T cells.